Born to be afraid? The neurogenetics of fear and punishment sensitivity

Throughout life, every individual is inevitably exposed to a variety of adverse events ranging from simple everyday stressors to traumatic experiences. However, people’s responses to different stressors vary greatly. Some people prove vulnerable and may develop mental illnesses like Post Traumatic Stress Disorder (PTSD) or other anxiety disorders. However, others are resilient and cope successfully with the same stressor. This raises the question: what determines whether we can cope with a stressful event or not? This thesis focuses on one specific biological factor: the genetic make-up we are born with. Hence, the main question of this thesis is: Are certain individuals ‘Born to be afraid’? To investigate this question, healthy human subjects provided genetic material and experienced different adverse events while their physiological reactions to these events were recorded. Based on a priori hypothesis, mainly derived from preclinical studies, specific genetic markers (so-called polymorphisms) were selected. In the first studies, the acquisition, expression and extinction of fear were investigated. Anxiety was evoked by electrical shocks, and startle reflex recordings were used to quantify the subjects’ fearful state. We showed, that genetic polymorphisms within the corticotroping-releasing hormone system and serotonin system are involved in fear acquisition and fear expression. Genetic variability within cannabinoid receptor 1, analogue to what has been reported in animals, modulated the extinction of fear. In another set of studies, subjects experienced punishment by means of monetary losses and were presented with unexpected novel events while an electroencephalogram was recorded. We found, that genetic polymorphisms within the serotonin and dopamine systems were associated with heightened neural sensitivity to these events. Do these findings support the conclusion that certain individuals are ‘Born to be afraid’? No, this would be an oversimplified interpretation of the findings reported in this thesis. Rather, the current results imply that in certain individuals genetic factors exist that predispose them to have stronger fear reactions and, via that route, potentially heightened anxiety. In sum, this thesis shows that our genetic make-up plays a role in adaptive responses to stressors in the environment, albeit a modest one. This sheds new light on why and how some individuals react adequately to stressors, while others fail to do so. With future replications of the present findings and additional molecular studies, the present data will contribute to our understanding of the neuropsychopharmacology of vulnerability and resilience towards psychiatric disorders. This may ultimately help in the development of novel or improvement of current clinical applications, such as pharmacological therapeutics.